BICYCLIC COMPOUNDS AS alpha4 beta2 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS

ABSTRACT

The present invention relates to novel bicyclic compounds of the formula (I), and their derivatives, prodrugs, tautomers, stereoisomers, polymorphs, solvates, hydrates, metabolites, N-oxides, pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their derivatives, prodrugs, tautomers, stereoisomers, polymorphs, solvates, hydrates, metabolites, N-oxides, pharmaceutically acceptable salts and compositions containing them. These compounds are useful in the treatment and prevention of various disorders that are related to α 4 β 2  nicotinic receptors.

FIELD OF INVENTION

The present invention relates to novel bicyclic compounds of the formula(I), and their derivatives, prodrugs, tautomers, stereoisomers,polymorphs, solvates, hydrates, metabolites, N-oxides, pharmaceuticallyacceptable salts and compositions containing them.

The present invention also relates to a process for the preparation ofabove said novel compounds, and their derivatives, prodrugs, tautomers,stereoisomers, polymorphs, solvates, hydrates, metabolites, N-oxides,pharmaceutically acceptable salts and compositions containing them.

These compounds are useful in the treatment and prevention of variousdisorders that are related to α₄β₂ nicotinic receptors.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChRs) or Neuronal nicotinicreceptors (NNRs) mediate a very wide range of physiological effects andhave been targeted for therapeutic treatment of various disorders.nAChRs belonging to the super family of ligand gated ion channels(LGIC), are widely distributed throughout the central nervous system(CNS) and the peripheral nervous system (PNS). The NNRs are understoodto play an important role in regulating CNS function and the release ofmany neurotransmitters. Typically, NNRs are constructed from apentameric assembly of subunit proteins. Seventeen subunits of nAChRshave been identified to date, which are identified as α2-α18, β1-β4, γ,δ, and ε. Of these subunits, eight neuronal α (α2 through α9) and threeneuronal β (β2 through β4), prominently exist in the mammalian brain.(See for examples, Monteggia L M et al., Cloning and transientexpression of genes encoding the human alpha4 and beta2 neuronalnicotinic acetylcholine receptor (nAChR) subunits, Gene: 1995,155:189-193; Graham A et al., Immunohistochemical localization ofnicotinic acetylcholine receptor subunits in human cerebellum,Neuroscience. 2002; 113:493-507). Multiple functionally distinct nAChRcomplexes also exist; as a homomeric functional pentamer or combinationsof different subunits can complex together (see for examples, Hogg, R. Cet al., Nicotinic acetylcholine receptors: from structure to brainfunction, Rev. Physiol, Biochem. Pharmacol, 2003, 147: 1-46).

The identification of a family of genes coding for the nAChRs andincreased knowledge of their expression and function in the centralnervous system have lead to the increasing attention concerning theirpotential as drug targets. (See examples, Hogg R. C et al., NicotinicAcetylcholine Receptors as Drug Targets, Curr. Drug Targets: CNS Neurol.Disord. 2004, 3: 123-130; Suto et al., Neuronal nicotinic acetylcholinereceptors as drug targets, Expert Opin. Ther. Targets 2004, 8: 61-64).

There are many potential therapeutic uses for neuronal nicotinic α₄β₂receptor ligands in humans based on direct effects and on indicationsfrom available scientific studies. Neuronal nicotinic α₄β₂ receptorshave been implicated in different therapies like cognitive disorders,including Alzheimer's disease, Parkinson's disease, Attentiondeficit/hyperactivity disorder, Schizophrenia and Tourette's syndrome(See examples, Newhouse et al., Effects of nicotinic stimulation oncognitive performance, Curr. Opin. Pharmacol. 2004, 4: 36-46; Levin E. Det al., Nicotinic Treatment for Cognitive Dysfunction, Curr. DrugTargets: CNS Neurol. Disord. 2002, 1: 423-431; Graham A. J. et al.,Human Brain Nicotinic Receptors, their Distribution and Participation inNeuropsychiatric Disorders, Curr. Drug Targets: CNS Neurol. Disord.2002, 1: 387-397; McEvoy J. P et al., The Importance of NicotinicAcetylcholine Receptors in Schizophrenia, Bipolar Disorder andTourette's Syndrome, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1:433-442).

Studies in a variety of rodent pain models have demonstrated that α₄β₂receptor ligands have the potential for highly efficacious treatments ina variety of pain states and inflammation. (See examples, Vincler etal., Neuronal nicotinic receptors as targets for novel analgesics,Expert Opin. Invest. Drugs, 2005, 14: 1191-1198; Decker M W et al., Thetherapeutic potential of nicotinic acetylcholine receptor agonists forpain control, Expert Opin Investig Drugs. 2001 October; 10(10):1819-30;Miao et. al., Central terminals of nociceptors are targets for nicotinesuppression of inflammation, Neuroscience 2004, 123: 777-84).

Significant efforts are being made to understand the hypercholinergicneurotransmission, which is associated with depressed mood statessuggesting that it may be mediated through excessive neuronal nicotinicreceptor activation and that the therapeutic actions of manyantidepressants may be, in part, mediated through inhibition of thesereceptors. Thus the neuronal nicotinic α₄β₂ receptor ligands mayrepresent a novel class of therapeutic agents for treating depressionand anxiety disorders (See examples, Shytle et al., Nicotinicacetylcholine receptors as targets for antidepressants, Mol. Psychiatry.2002, 7: 525-35; Shytle et al., Neuronal nicotinic receptor inhibitionfor treating mood disorders: preliminary controlled evidence withmecamylamine, Depress. Anxiety, 2002, 16: 89-92). Recent studies havealso been reported that the nAChRs play a role in neurodegenerativedisorders. The nicotine and subtype selective nAChR ligands can provideneuroprotection in in-vitro cell culture systems and in in-vivo studiesin animal models of such disorders. (See examples, O'Neill et al., Therole of neuronal nicotinic acetylcholine receptors in acute and chronicneurodegeneration, Curr. Drug Targets: CNS Neurol. Disord. 2002, 1:399-411).

The α₄β₂ nAChR subtype has the highest affinity for nicotine and is theprimary candidate for mediating nicotine's central effects. Chronicnicotine exposure (in humans, animals and cell culture systems) leads toan increase in the number of α₄β₂ nAChR (upregulation), with functionalimplications for withdrawal. These studies suggested that the neuronalnicotinic α₄β₂ receptor ligands play a critical role in the treatment ofaddiction. (Dwoskin et al., A novel mechanism of action and potentialuse for lobeline as a treatment for psychostimulant abuse, Biochem.Pharmacol. 2002, 63: 89-98; Coe et al., 3,5-Bicyclic aryl piperidines: anovel class of α₄β₂ nAChR partial agonists for smoking cessation,Bioorg. Med. Chem. Lett. 2005, 15: 4889-97). The α₄β₂ receptor ligandsare also expected to be of use in the treatment of obesity (Li et al.,Nicotine, body weight and potential implications in the treatment ofobesity, Curr. Top. Med. Chem. 2003, 3: 899-919).

Taken together, the above studies strongly suggest that compounds whichare α₄β₂ receptor modulators, i.e. ligands, may be useful fortherapeutic indications including, the treatment of diseases associatedwith a deficit in memory, cognition and learning such as Alzheimer's andattention deficit disorder; the treatment of personality disorders suchas schizophrenia; the treatment of behavioral disorders, e.g. anxiety,depression and obsessive compulsive disorders; the treatment of pain andinflammation; the treatment of motion or motor disorders such asParkinson's disease and epilepsy; the treatment of diseases associatedwith neurodegeneration such as stroke or head trauma or withdrawal fromdrug addiction including addiction to nicotine, alcohol and othersubstances of abuse and obesity.

Patent publications WO2008057938 (A1), US20040192673 (A1) and EP296560(B1) disclose series of compounds as ligands of nicotinic acetylcholinereceptors and are claimed to be useful in the treatment of various CNSdisorders. While some nicotinic acetylcholine receptor compounds havebeen disclosed, there continues to be a need for compounds that areuseful for modulating nicotinic acetylcholine receptors. In our researchin area of nicotinic acetylcholine receptors, we found that bicycliccompounds of formula (I) demonstrate very high nicotinic acetylcholinereceptor affinity. Therefore, it is an object of this invention toprovide compounds, which are useful as therapeutic agents in thetreatment/prevention of a variety of central nervous system disorders ordisorders affected by the α₄β₂ nicotinic receptors.

SUMMARY OF THE INVENTION

The present invention relates to novel bicyclic compounds of the formula(I), and their derivatives, prodrugs, tautomers, stereoisomers,polymorphs, solvates, hydrates, metabolites, N-oxides, pharmaceuticallyacceptable salts and compositions containing them.

wherein R represents aryl or heteroaryl;

R₁ represents hydrogen, alkyl or cycloalkyl;

R₂ represents hydrogen, alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkoxy, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl;

R₃ represents hydrogen, hydroxy, halogen, oxo, thio, nitro, amide,amine, carboxylic, alkyl, alkoxy, cycloalkyl, cycloalkylalkyl,cycloalkoxy, haloalkyl, haloalkoxy, heterocyclyl or heterocyclylalkyl;

“X” represents C, O, N, S;

“m” represents 1 to 4;

“n” represents 1 to 2;

“p” represents 0 to 2;

“q” represents 0 to 1.

The present invention relates to use of a therapeutically effectiveamount of compound of formula (I), to manufacture a medicament in thetreatment and prevention of various disorders that are related to α₄β₂nicotinic receptors.

Specifically, the compounds of this invention are useful in thetreatment of various disorders such as anxiety, alzheimer's disease,depression, convulsive disorders, obsessive-compulsive disorders,cognitive memory disorders, ADHD (Attention DeficientDisorder/Hyperactivity Syndrome), pain, inflammation, personalitydisorders, psychosis, paraphrenia, psychotic depression, parkinson'sdisease, mania, schizophrenia, panic disorders, sleep disorders,withdrawal from drug abuse syndrome, stroke, head trauma, mild cognitiveimpairment, neurodegenerative disorders and obesity.

In another aspect, the invention relates to pharmaceutical compositionscontaining a therapeutically effective amount of at least one compoundof formula (I), and their derivatives, prodrugs, tautomers,stereoisomers, polymorphs, solvates, hydrates, metabolites, N-oxides andpharmaceutically acceptable salts thereof, in admixture with at leastone suitable carrier, diluents, adjuvants or excipients.

In another aspect, the invention also provides a radiolabeled compoundof formula (I) for use in medical diagnosis or therapy, as well as theuse of a radiolabeled compound of formula (I) to prepare a medicamentuseful in the treatment of various disorders that are related to α₄β₂nicotinic receptors.

In another aspect, the invention relates to the use of a compoundaccording to the present invention in combination with at least onefurther active ingredient for manufacture of a medicament for thetreatment or prevention of diseases and conditions.

In still another aspect, the invention relates to compositionscomprising and methods for using compounds of formula (I).

In yet another aspect, the invention further relates to the process forpreparing compounds of formula (I) and their derivatives, prodrugs,tautomers, stereoisomers, polymorphs, solvates, hydrates, metabolites,N-oxides and pharmaceutically acceptable salts.

Representative compounds of the present invention include thosespecified below and their derivatives, prodrugs, tautomers,stereoisomers, polymorphs, solvates, hydrates, metabolites, N-oxides andpharmaceutically acceptable salts. The present invention should not beconstrued to be limited to them.

-   3-(Pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane dihydrochloride;-   2-Methyl-3-(pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   3-(2-Methylpyridin-3-yl-oxymethyl)-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(2-Chloropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(2-Chloropyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(2-Fluoropyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(5-Bromopyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane tartrate;-   3-(2-Fluoropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane    tartrate;-   3-(2-Fluoropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane    tartrate;-   3-(2-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   2-Methyl-3-(2-methylpyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   2-Methyl-3-(2-methylpyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   3-(2-Chloropyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   3-(2-Fluoropyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   3-(5-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   3-(5-Bromopyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane    dihydrochloride;-   3-(2-Methylpyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acid    amide;-   5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acid;-   3-(2-Methoxypyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   3-(2-Isopropoxypyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   [5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]-methanol;-   3-(2-Methoxymethylpyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   [5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-ylmethyl]methylamine;-   5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic    acid amide;-   5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic    acid;-   3-(2-Methoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   3-(2-Isopropoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;-   [5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]methanol;-   Methyl-[5-(2-methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-ylmethyl]amine;-   5-[1-(2-Azabicyclo[3.1.0]hex-3-yl)-ethoxy]pyridin-2-ylamine;-   {5-[1-(2-Azabicyclo[3.1.0]hex-3-yl)-ethoxy]pyridin-2-yl}methylamine;-   [5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]dimethylamine;-   3-(2-Pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane;-   5-[1-(2-Methyl-2-azabicyclo[3.1.0]hex-3-yl)ethoxy]pyridin-2-ylamine;-   Methyl-{5-[1-(2-methyl-2-azabicyclo[3.1.0]hex-3-yl)ethoxy]pyridin-2-yl}amine;-   Dimethyl-[5-(2-methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]amine;-   2-Methyl-3-(2-pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;-   3-(Pyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;-   3-(2-Methylpyridin-5-yloxymethyl)-2-azabicyclo[4.1.0]heptane;-   3-(2-Methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;-   3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;-   2-Methyl-3-(2-methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;-   3-(5-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[4.1.0]heptane;-   4-[2-(Pyridin-3-yloxy)ethyl]-2-azabicyclo[3.1.0]hexane;-   4-[2-(5-Chloropyridin-3-yloxy)ethyl]-2-methyl-2-azabicyclo[3.1.0]hexane;-   3-(Pyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane hydrochloride    and 3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane    hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below:

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “alkyl” means straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond. Exemplary “alkyl”groups include methyl, ethyl, n-propyl, iso-propyl and the like.

The term “alkoxy” means an alkyl group attached via an oxygen linkage tothe rest of the molecule. Exemplary “alkoxy” groups include methoxy,ethoxy, propyloxy, iso-propyloxy and the like.

The term “cycloalkyl” means non-aromatic mono or multi cyclic ringsystems of 3 to 12 carbon atoms. Exemplary “cycloalkyl” groups includecyclopropyl, cyclobutyl, cyclopenty and the like. “cycloalkyl” groupsmay be substituted or unsubstituted, and optionally substituents may beselected from the group consisting of hydrogen, hydroxy, halogen, nitro,cyano, thio, oxo, carboxylic, amine, amide, alkyl, alkenyl, alkynyl,alkoxy, haloalkyl or haloalkoxy.

The term “cycloalkylalkyl” means cycloalkyl group directly attached toalkyl group. Exemplary “cycloalkylalkyl” groups includecyclopropylmethyl, cyclobutylethyl, cyclopentylethyl and the like.“cycloalkylalkyl” groups may be substituted or unsubstituted, andoptionally substituents may be selected from the group consisting ofhydrogen, hydroxy, halogen, nitro, cyano, thio, oxo, carboxylic, amine,amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or haloalkoxy.

The term “cycloalkoxy” means non-aromatic mono or multi cyclic ringsystems of 3 to 12 carbon atoms. Exemplary “cycloalkoxy” groups includecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike. “cycloalkoxy” groups may be substituted or unsubstituted, andoptionally substituents may be selected from the group consisting ofhydrogen, hydroxy, halogen, nitro, cyano, thio, oxo, carboxylic, amine,amide, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or haloalkoxy.

The term “haloalkyl” means straight or branched chain alkyl radicalscontaining one to three carbon atoms and includes fluoromethyl,difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl,difluoroethyl and the like.

The term “haloalkoxy” means straight or branched chain alkoxy radicalscontaining one to three carbon atoms and includes fluoromethoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy,difluoroethoxy and the like.

The term “aryl” means monocyclic or bicyclic aromatic ring system, whichmay be substituted or unsubstituted, and optionally substituents may beselected from the group consisting of hydrogen, hydroxy, halogen, nitro,thio, oxo, carboxylic, amine, amide, alkyl, alkoxy, haloalkyl orhaloalkoxy.

The term “heteroaryl” means organic compounds that contain a ringstructure containing atoms in addition to carbon such as sulfur, oxygenor nitrogen, as part of the ring. These additional atoms may be repeatedmore than once in ring. These rings may be either simple aromatic ringsor non-aromatic rings and includes pyridine, pyrimidine, benzothiopheneand the like, which may be substituted or unsubstituted, and optionallysubstituents may be selected from the group consisting of hydrogen,hydroxy, halogen, nitro, thio, oxo, carboxylic, amine, amide, alkyl,alkoxy, haloalkyl or haloalkoxy.

The term “heterocyclyl” means 3 to 8-membered rings, whose ringstructures include 1 to 3 heteroatoms; these additional atoms may berepeated more than once in ring. “heterocyclyl” groups may besubstituted or unsubstituted, and optionally substituents may beselected from the group consisting of hydrogen, hydroxy, halogen, nitro,cyano, thio, oxo, carboxylic, amine, amide, alkyl, alkenyl, alkynyl,alkoxy, haloalkyl or haloalkoxy.

The term “heterocyclylalkyl” means heterocyclyl ring directly attachedto alkyl group.

The term “stereoisomers” is a general term for all isomers of theindividual molecules that differ only in the orientation of their atomsin space. It includes mirror image isomers (enantiomers), geometric(cis-trans) isomers and isomers of compounds with more than one chiralcentre that are not mirror images of one another (diastereomers).

The term “prodrug” is used to refer to a compound capable of converting,either directly or indirectly, into compounds described herein by theaction of enzymes, gastric acid and the like under in vivo physiologicalconditions (e.g., enzymatic oxidation, reduction and/or hydrolysis).

The term “solvate” is used to describe a molecular complex betweencompounds of the present invention and solvent molecules. Examples ofsolvates include, but are not limited to, compounds of the invention incombination water, isopropanol, ethanol, methanol, dimethylsulfoxide(DMSO), ethyl acetate, acetic acid, ethanolamine or mixtures thereof.

The term “hydrate” can be used when said solvent is water. It isspecifically contemplated that in the present invention one solventmolecule can be associated with one molecule of the compounds of thepresent invention, such as a hydrate. Furthermore, it is specificallycontemplated that in the present invention, more than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a dihydrate. Additionally, it is specificallycontemplated that in the present invention less than one solventmolecule may be associated with one molecule of the compounds of thepresent invention, such as a hemihydrate. Furthermore, solvates of thepresent invention are contemplated as solvates of compounds of thepresent invention that retain the biological effectiveness of thenon-hydrate form of the compounds.

The term “tautomers” include readily interconvertible isomeric forms ofa compound in equilibrium. The enol-keto tautomerism is an example.

The term “polymorphs” include crystallographically distinct forms ofcompounds with chemically identical structures.

The term “metabolite” refers to substance produced by metabolism.

The term “derivative” refers to a compound obtained from a compoundaccording to formula (I), and their tautomers, stereoisomers,polymorphs, solvates, hydrates, N-oxides and pharmaceutically acceptablesalts thereof, by a simple chemical process converting one or morefunctional groups such as by oxidation, hydrogenation, alkylation,esterification, halogenation and the like.

The term “schizophrenia” means schizophrenia, schizophreniform andschizoaffective disorder.

The term “psychotic disorder” refers to delusions, prominenthallucinations, disorganized speech or disorganized or catatonicbehavior. See Diagnostic and Statistical Manual of Mental Disorder,fourth edition, American Psychiatric Association, Washington, D.C.

The terms “treating”, “treat” or “treatment” embrace all the meaningssuch as preventative, prophylactic and palliative.

The phrase “pharmaceutically acceptable salts” indicates that thesubstance or composition must be compatible chemically and/ortoxicologically, with the other ingredients comprising a formulation,the mammal being treated therewith.

The phrase “Therapeutically effective amount” is defined as ‘an amountof a compound of the present invention that (i) treats or prevents theparticular disease, condition or disorder (ii) attenuates, amelioratesor eliminates one or more symptoms of the particular disease, conditionor disorder (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition or disorder described herein’.

Commercial reagents were utilized without further purification. Roomtemperature refers to 25-30° C. IR were taken using KBr and in solidstate. Unless otherwise stated, all mass spectra were carried out usingESI conditions. ¹H-NMR spectra were recorded at 400 MHz on a Brukerinstrument. Deuterated chloroform (99.8% D) was used as solvent. TMS wasused as internal reference standard. Chemical shift values are expressedin parts per million (δ) values. The following abbreviations are usedfor the multiplicity for the NMR signals: s=singlet, bs=broad singlet,d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=doubledoublet, dt=double triplet, tt=triplet of triplets, m=multiplet.Chromatography refers to column chromatography performed using 100-200mesh silica gel and executed under nitrogen pressure (flashchromatography) conditions.

The compounds of the invention can be used in combination with othertherapeutic agents or approaches used to treat or prevent the conditionslisted above. Such agents or approaches include 5-HT₁₋₇ receptors, GABAinverse agonists and other nicotinic acetylcholine receptors.

In the combination of the present invention, the compounds of thepresent invention and the above mentioned combination partners may beadministered separately (e.g. kit of parts) or together in onepharmaceutical composition (e.g. capsule or tablet). In addition, theadministration of one element of the combination of the presentinvention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination of the presentinvention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination. If the compoundsof the present invention and the one or more additional activeingredient are present in separate formulations these separateformulations may be administered simultaneously or sequentially.

Therefore, the invention relates to the use of a compound according tothe present invention in combination with at least one further activeingredient for the manufacture of a medicament for the treatment orprevention of diseases and conditions.

Numerous radioisotopes are readily available including isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, iodine,fluorine, bromine & chlorine. For example: ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹⁸F, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ⁸²Br & ³⁶Cl.

A compound of general formula (I) can be radiolabeled by using standardtechniques known in organic chemistry. Alternatively, compound offormula (I) radiolabeled with radioisotope as a substituent in one ofthe starting materials or in an intermediate used in the synthesis ofthe compound of formula (I). For example, see Arthur Murry III, D. LloydWilliams; Organic Synthesis with Isotopes, vol. I and II, IntersciencePublishers Inc., N.Y. (1958) and Melvin Calvin et al. Isotopic CarbonJohn Wiley and Sons Inc., N.Y (1949).

Synthesis of radiolabeled compounds may be conveniently performed by aradioisotope supplier specializing in custom synthesis of radiolabeledprobe compounds, such as Amersham Corporation, Arlington Heights, Ill.;Cambridge Isotopes Laboratories, Inc. Andover, Mass.; WizardLaboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena,Kans.; American Radiolabeled Chemicals, Inc. & St. Louis, Mo.;

Radiolabeled analogues of compound of formula (I) may be used inclinical studies to evaluate the role of α₄β₂ nicotinic receptor ligandsin a variety of disease areas, where α₄β₂ nicotinic receptor ligands arebelieved to be involved. Radiolabeled compounds of formula (I) areuseful as imaging agents and biomarker for medical therapy anddiagnosis. Such radiolabeled compounds are also useful aspharmacological tools for studying α₄β₂ nicotinic receptor functions andactivity. For example, isotopically labeled compounds are particularlyuseful in SPECT (single photon emission compound tomography) and in PET(positron emission tomography).

Pharmaceutical Compositions

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice.

The pharmaceutical compositions of the present invention may beformulated in a conventional manner using one or more pharmaceuticallyacceptable carriers. Thus, the active compounds of the invention may beformulated for oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or a formsuitable for administration by inhalation or insufflations.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol) and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueous vehiclesand may contain formulating agents such as suspending, stabilizingand/or dispersing agents. Alternatively, the active ingredient may be inpowder form for reconstitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof an aerosol spray from a pressurized container or a nebulizer or froma capsule using an inhaler or insufflators. In the case of a pressurizedaerosol, a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas and the dosage unit may be determined by providing avalve to deliver a metered amount. The medicament for pressurizedcontainer or nebulizer may contain a solution or suspension of theactive compound while for a capsule; it preferably should be in the formof powder. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

Aerosol formulations for treatment of the conditions referred to above(e.g., migraine) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

An effective amount of a compound of general formula (I) or theirderivatives as defined above can be used to produce a medicament, alongwith conventional pharmaceutical auxiliaries, carriers and additives.

Such a therapy includes multiple choices: for example, administering twocompatible compounds simultaneously in a single dose form oradministering each compound individually in a separate dosage; or ifrequired at same time interval or separately in order to maximize thebeneficial effect or minimize the potential side-effects of the drugsaccording to the known principles of pharmacology.

The dose of the active compounds can vary depending on factors such asthe route of administration, age and weight of patient, nature andseverity of the disease to be treated and similar factors. Therefore,any reference herein to a pharmacologically effective amount of thecompounds of general formula (I) refers to the aforementioned factors. Aproposed dose of the active compounds of this invention, for eitheroral, parenteral, nasal or buccal administration, to an average adulthuman, for the treatment of the conditions referred to above, is 0.1 to200 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Methods of Preparation

The compounds of formula (I) can be prepared by Scheme I as shown below.

The compound of formula (8) is allowed to react with hydroxy compound offormula (9) to form compound of formula (10). The compound of formula(10) is converted to deprotected compound of formula (11). The compoundof formula (11) is converted to compound of formula (I).

In the first step of the above preparation, the compound of formula (8)is reacted with compound of formula (9) using Mitsunobu reactionconditions to obtain compound of formula (10). This reaction ispreferably carried out in a solvent such as tetrahydrofuran, toluene,dimethylformamide, dimethyl sulfoxide, dimethyl ether and the like or amixture thereof and preferably by using tetrahydrofuran. The reactionmay be affected in the presence of reagents such as diethylazodicarboxylate, diisopropyl azodicarboxylate, phosphino reagents, suchas tricyclohexylphosiphine, triorthotolylphosphine, triphenyl phosphineor mixtures thereof and preferably by using triphenyl phosphine. Thereaction temperature may range from −10° C. to 50° C. based on thechoice of solvent and preferably at a temperature in the range from −5°C. to 50° C. The duration of the reaction may range from 12 to 20 hours,preferably from a period of 14 to 18 hours.

In the second step of the above preparation, the compound of formula(10) is converted to the compound of formula (11). This reaction ispreferably carried out using hydrochloric acid or trifluoro acid in asolvent such as ethanol, tetrahydrofuran, toluene, acetic acid, ethylacetate, isopropanol, diethyl ether, dichloromethane and the like or amixture thereof and preferably by using isopropanol. The duration of thereaction may range from 1 to 4 hours, preferably from a period of 1 to 3hours.

In the third step of the above preparation, the compound of formula (11)is converted in to general formula (I). This reaction is preferablycarried out in a solvent such as ethanol, tetrahydrofuran, toluene,water, dimethylformamide, dimethyl sulfoxide and the like or a mixturethereof. The reaction temperature may range from 40° C. to 120° C. basedon the choice of solvent and preferably at a temperature in the rangefrom 60° C. to 100° C. The duration of the reaction may range from 1 to5 hours, preferably from a period of 2 to 4 hours.

The starting material of formula (8) is synthesized as described in step(vii) of preparation 1. This starting material may be commerciallyavailable or they may be prepared by conventional methods or bymodifying the existing known processes. The starting material of formula(9) may be commercially available or they may be prepared byconventional methods or by modification, using known processes.

Compounds obtained by the above method of preparation of the presentinvention can be transformed into another compound of this invention byfurther chemical modifications using well-known reactions such asoxidation, reduction, protection, deprotection, rearrangement reaction,halogenation, hydroxylation, alkylation, alkylthiolation, demethylation,O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation,N-cyanation, N-sulfonylation, coupling reaction using transition metalsand the like.

If necessary, any one or more than one of the following steps can becarried out,

i) Converting a compound of the formula (I) into another compound of theformula (I)ii) Removing any protecting groups; oriii) Forming a pharmaceutically acceptable salt, solvate or a prodrugthereof.

Process (i) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation, andnucleophilic or electrophilic aromatic substitution and ester hydrolysisor amide bond formation.

In process (ii) examples of protecting groups and the means for theirremoval can be found in T. W. Greene ‘Protective Groups in OrganicSynthesis’ (J. Wiley and Sons, 1991). Suitable amine protecting groupsinclude sulfonyl (e.g. tosyl), acyl (e.g. acetyl,2′,2′,2′-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)and arylalkyl (eg. benzyl), which may be removed by hydrolysis (e.g.using an acid such as hydrochloric or trifluoroacetic acid) orreductively (e.g. hydrogenolysis of a benzyl group or reductive removalof a 2′,2′,2′-trichloroethoxycarbonyl group using zinc in acetic acid)as appropriate. Other suitable amine protecting groups includetrifluoroacetyl, which may be removed by base catalyzed hydrolysis or asolid phase resin bound benzyl group, such as a Merrifield resin bound2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acidcatalyzed hydrolysis, for example with trifluoroacetic acid.

In process (iii) halogenation, hydroxylation, alkylation and/orpharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative as describedearlier in detail.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. diastereomers and enantiomers) and theinvention extends to each of these stereoisomeric forms and to mixturesthereof including racemates. The different stereoisomeric forms may beseparated from one another by the usual methods or any given isomer maybe obtained by stereospecific or asymmetric synthesis. The inventionalso extends to tautomeric forms and mixtures thereof.

The stereoisomers as a rule are generally obtained as racemates that canbe separated into the optically active isomers in a manner known per se.In the case of the compounds of general formula (I) having an asymmetriccarbon atom the present invention relates to the D-form, the L-form andD,L-mixtures and in the case of compound of general formula (I)containing a number of asymmetric carbon atoms, the diastereomeric formsand the invention extends to each of these stereo isomeric forms and tomixtures thereof including racemates. Those compounds of general formula(I) which have an asymmetric carbon and as a rule are obtained asracemates can be separated one from the other by the usual methods, orany given isomer may be obtained by stereo specific or asymmetricsynthesis. However, it is also possible to employ an optically activecompound from the start, a correspondingly optically active enantiomericor diastereomeric compound then being obtained as the final compound.

The stereoisomers of compounds of general formula (I) may be prepared byone or more ways presented below:

i) One or more of the reagents may be used in their optically activeform.ii) Optically pure catalyst or chiral ligands along with metal catalystmay be employed in the reduction process. The metal catalyst may beRhodium, Ruthenium, Indium and the like. The chiral ligands maypreferably be chiral phosphines (Principles of Asymmetric synthesis, J.E. Baldwin Ed., Tetrahedron series, 14, 311-316).iii) The mixture of stereoisomers may be resolved by conventionalmethods such as forming diastereomeric salts with chiral acids or chiralamines or chiral amino alcohols, chiral amino acids. The resultingmixture of diastereomers may then be separated by methods such asfractional crystallization, chromatography and the like, which isfollowed by an additional step of isolating the optically active productby hydrolyzing the derivative (Jacques et. al., “Enantiomers, Racematesand Resolution”, Wiley Interscience, 1981).iv) The mixture of stereoisomers may be resolved by conventional methodssuch as microbial resolution, resolving the diastereomeric salts formedwith chiral acids or chiral bases.

Chiral acids that can be employed may be tartaric acid, mandelic acid,lactic acid, camphorsulfonic acid, amino acids and the like. Chiralbases that can be employed may be cinchona alkaloids, brucine or a basicamino acid such as lysine, arginine and the like. In the case of thecompounds of general formula (I) containing geometric isomerism thepresent invention relates to all of these geometric isomers.

Suitable pharmaceutically acceptable salts will be apparent to thoseskilled in the art and include those described in J. Pharm. Sci., 1977,66, 1-19, such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, malic,tartaric, benzoic, p-toluic, p-toluenesulfonic, methanesulfonic ornaphthalenesulfonic acid. The present invention includes, within itsscope, all possible stoichiometric and non-stoichiometric forms.

The pharmaceutically acceptable salts forming a part of this inventionmay be prepared by treating the compound of formula (I) with 1-6equivalents of a base such as sodium hydride, sodium methoxide, sodiumethoxide, sodium hydroxide, potassium t-butoxide, calcium hydroxide,calcium acetate, calcium chloride, magnesium hydroxide, magnesiumchloride and the like. Solvents such as water, acetone, ether, THF,methanol, ethanol, t-butanol, dioxane, isopropanol, isopropyl ether ormixtures thereof may be used.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form and if crystalline, may optionally be solvated, eg.as the hydrate. This invention includes within its scope stoichiometricsolvates (eg. hydrates) as well as compounds containing variable amountsof solvent (eg. water).

Various polymorphs of compound of general formula (I) forming part ofthis invention may be prepared by crystallization of compound of formula(I), under different conditions. For example, using different solventscommonly used or their mixtures for recrystallization, crystallizationsat different temperatures; various modes of cooling ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by gradual or fast cooling of compound after heating ormelting. The presence of polymorphs may be determined by solid probe NMRspectroscopy, IR spectroscopy, differential scanning calorimetry, powderX-ray diffraction or such other techniques.

Pharmaceutically acceptable solvates of the compounds of formula (I)forming part of this invention may be prepared by conventional methodssuch as dissolving the compounds of formula (I) in solvents such aswater, methanol, ethanol, mixture of solvents such as acetone-water,dioxane-water, N,N-dimethylformamide-water and the like, preferablywater and recrystallizing by using different crystallization techniques.

Prodrugs of the present application may be prepared from compound offormula (I) by using known process. Conventional procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in Design of prodrugs (1985); Wihnan, Biochem Soc. Trans.1986, 14, 375-82; Stella et al., Prodrugs: A chemical approach totargeted drug delivery in directed drug delivery, 1985, 247-67, each ofwhich is incorporated by reference herein in its entirety.

Tautomers of compounds of formula (I) can be prepared by using knownprocess. Procedures for preparation of suitable Tautomers are described,for example in Smith M B, March J (2001). Advanced Organic Chemistry(5th ed.) New York: Wiley Interscience. pp. 1218-1223 and Katritzky A R,Elguero J, et al. (1976). The Tautomerism of heterocycles. New York:Academic Press.

N-Oxides of compounds of formula (I) can be prepared by using knownprocess. Procedures for preparation of suitable N-Oxides are described,March's Advanced Organic Chemistry: Reactions, Mechanisms, and StructureMichael B. Smith, Jerry March Wiley-Interscience, 5th edition, 2001.

Hydrates of compounds of formula (I) can be prepared by using knownprocess.

In the case of the compounds of general formula (I) containing geometricisomerism the present invention relates to all of these geometricisomers.

EXAMPLES

The novel compounds of the present invention were prepared according tothe following procedures, using appropriate materials and are furtherexemplified by the following specific examples. The most preferredcompounds of the invention are any or all of those specifically setforth in these examples. These compounds are not, however, to beconstrued as forming the only genus that is considered as the inventionand any combination of the compounds or their moieties may itself form agenus. The following examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand process of the following preparative procedures can be used toprepare these compounds.

Preparation 1: Preparation of (2-Azabicyclo[3.1.0]hex-3-yl)methanol Step(i): Preparation of5-(tert-Butyldiphenylsilanyloxymethyl)pyrrolidin-2-one

To an ice cold solution of 5-Hydroxymethylpyrrolidin-2-one (5 grams,43.4 mmol) in dichloromethane (174 mL) was added imidazole (6.5 grams,95.5 mmol), 4-dimethylaminopyridine (530 mg, 4.3 mmol) followed bytert-butyldiphenylsilyl chloride (12.53 grams, 45.57 mmol). The reactionmixture was gradually warmed to room temperature and upon completion of2 hours, diluted with dichloromethane, washed with water, brine anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to obtain title compound of 15.37 grams, as gummyliquid, which was taken up for the next reaction without furtherpurification.

¹H-NMR (CDCl₃): 7.65-7.63 (m, 4H), 7.45-7.37 (m, 6H), 3.84-3.77 (m, 1H),3.62 (dd, J=3.9, 10.2 Hz, 1H), 3.50 (dd, J=7.7, 10.2 Hz, 1H), 2.40-2.30(m, 2H), 2.20-2.11 (m, 1H), 1.76-1.67 (m, 1H), 1.05 (s, 9H);

Mass (m/z): 354 [M+H⁺].

Step (ii): Preparation of 2-(tert-Butyldiphenylsilanyloxymethyl)-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of above obtained compound (15.35 grams, 43.42mmol) in acetonitrile (174 mL) was added 4-dimethylaminopyridine (6.36grams, 52.1 mmol) and tert-butyldicarbonate (11 mL, 47.8 mmol). Afterstirring for 16 hours at room temperature the reaction mixture wasdiluted with ethyl acetate, washed with water, brine and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto obtain crude product, which was purified by flash columnchromatography using 230-400 mesh silica gel to obtain title compound of18.28 grams as solid. Yield: 93% for two steps

Melting Range: 105.9-108.3° C.

IR (cm⁻¹): 2953, 2930, 1747, 1709, 1471, 1431, 1311, 1111, 742, 705;

¹H-NMR (CDCl₃): 7.64-7.56 (m, 4H), 7.46-7.35 (m, 6H), 4.22-4.19 (m, 1H),3.89 (dd, J=4.2, 10.5 Hz, 1H), 3.70 (dd, J=2.3, 10.5 Hz, 1H), 2.78 (ddd,J=10.4, 10.4, 17.6 Hz, 1H), 2.44 (ddd, J=3.2, 8.8, 17.6 Hz, 1H),2.22-2.07 (m, 2H), 1.43 (s, 9H), 1.04 (s, 9H);

Mass (m/z): 454 [M+H⁺].

Step (iii): Preparation of2-(tert-Butyldiphenylsilanyloxymethyl)-5-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

To the stirred solution of above obtained compound (18.27 grams, 40.28mmol) in tetrahydrofuran (160 mL) at −78° C., was added a solution oflithiumtriethylborohydride (1M in tetrahydrofuran, 44.3 mL). Afterstirring for 1 hour, the reaction mixture was quenched by addingsaturated solution of sodiumbicarbaonate (68 mL). The reaction mixturewas warmed to 0° C., hydrogen peroxide (30% w/v, 1.3 mL) was added andstirred for 20 minutes. Two, layers were separated, the aqueous layerwas extracted with dichloromethane and the combined organic layer wasdried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to obtain title compound of 20.0 grams as gummy liquid,which was sufficiently pure enough to take up for the next reaction.Yield: 95.7%.

IR (cm⁻¹): 3444, 2960, 2931, 1681, 1392, 1166, 1112, 702;

¹H-NMR (CDCl₃): 7.71-7.60 (m, 4H), 7.45-7.32 (m, 6H), 5.52-5.43 (m, 1H),4.05-3.96 (m, 1H), 3.90-3.82 (m, 1H), 3.75-3.52 (m, 2H), 2.25-2.15 (m,1H), 2.10-1.82 (m, 3H), 1.51 (s, 3H), 1.34 (s, 6H), 1.06 (s, 9H);

Mass (m/z): 456 [M+H⁺].

Step (iv): Preparation of2-(tert-Butyldiphenylsilanyloxymethyl)-5-methoxypyrrolidine-1-carboxylicacid tertbutyl ester

To an ice cold solution of above obtained compound (18.34 grams, 40.2mmol) in methanol (160 mL), was added pyridinium paratoluene sulfonate(1.0 grams, 4.02 mmol). The reaction mixture was gradually warmed toroom temperature and stirred for 2 hours. Triethylamine (1.2 mL, 8.04mmol) was added and the volatiles were removed under reduced pressure toobtain a crude product which was purified by flash column using 230-400mesh silica gel to obtain isomeric mixture of title compound of 18.1grams as gummy liquid. Yield: 95.7%.

IR (cm⁻¹): 2958, 2931, 1701, 1390, 1366, 1163, 1112, 1085, 757, 702;

¹H-NMR (CDCl₃): 7.70-7.65 (m, 4H), 7.45-7.35 (m, 6H), 5.28-5.12 (m, 1H),4.05-3.85 (m, 2H), 3.70-3.50 (m, 1H), 3.26 (s, 3H), 2.25-2.05 (m, 2H),1.95-1.85 (m, 1H), 1.80-1.70 (m, 1H), 1.45 (s, 3H), 1.33 (s, 6H), 1.05(s, 9H);

Mass (m/z): 492 [M+Na⁺].

Step (v): Preparation of2-(tert-Butyldiphenylsilanyloxymethyl)-2,3-dihydropyrrole-1-carboxylicacid tert-butyl ester

A mixture of above obtained compound (18.1 grams, 38.5 mmol) andammonium chloride (311 mg, 5.7 mmol) was heated at 150° C. under reducedpressure (50 mbar) for 1 hour. The reaction mixture was cooled to roomtemperature and purified by flash column using 230-400 mesh silica gelto obtain title compound of 14.6 grams as gummy liquid. Yield: 86.5%.

IR (cm⁻¹): 2959, 2930, 2857, 1701, 1404, 1132, 1112, 762, 741, 701;

¹H-NMR (CDCl₃): 7.66-7.60 (m, 4H), 7.45-7.32 (m, 6H), 6.49 (d, J=43.3Hz, 1H), 4.95 (d, J=34.1 Hz, 1H), 4.25 (d, J=42.0 Hz, 1H), 3.90-3.58 (m,2H), 2.90-2.65 (m, 2H), 1.46 (s, 3H), 1.32 (s, 6H), 1.04 (s, 9H);

Mass (m/z): 438 [M+H⁺].

Step (vi): Preparation of3-(tert-Butyldiphenylsilanyloxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylicacid tert-butyl ester

To an ice cold solution of above obtained compound (2.0 grams, 4.56mmol) in dichloromethane (18 mL) was added a solution of diethylzinc (1Min hexane, 5.0 mL), followed by diiodomethane (0.55 mL, 6.84 mmol) overa period of 15 minutes and stirred for 30 minutes. The reaction mixturewas gradually warmed to room temperature and stirred for 3 hours. The pHof the reaction mixture was adjusted to 8 by addition of saturatedsodium bicarbonate solution. Two layers were separated and the aqueouslayer was extracted with dichloromethane. The combined organic layer waswashed with brine, dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure to obtain crude product, which waspurified by flash column chromatography using 230-400 mesh silica gel toobtain to obtain title compound of 1.5 grams as gummy liquid. Yield:73%.

IR (cm⁻¹): 2960, 2931, 2857, 1698, 1391, 1178, 1130, 1112, 1090, 702;

¹H-NMR (CDCl₃): 7.68-7.62 (m, 4H), 7.44-7.32 (m, 6H), 3.90-3.80 (m, 1H),3.74-3.68 (m, 2H), 3.22-3.13 (m, 1H), 2.40-2.27 (m, 1H), 2.08-1.96 (m,1H), 1.52-1.48 (m, 1H), 1.40 (s, 9H), 1.05 (s, 9H), 0.90-0.80 (m, 1H),0.38-0.30 (m, 1H);

Mass (m/z): 452 [M+H⁺].

Step (vii): Preparation of3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butylester

To an ice cold solution of above obtained compound (16.8 grams, 37.1mmol) in dry tetrahydrofuran (104 mL) was added tetrabutylammoniumfluoride (1M, in tetrahydrofuran 37.1 mL) over a period of 10 minutes.The reaction mixture was gradually warmed to room temperature andstirred for 12 hours. The volatiles were removed under reduced pressureto obtain a crude product, which was purified by flash columnchromatography to obtain title compound of 7.0 grams as gummy liquid.Yield: 88.6%.

IR (cm⁻¹): 3417, 2976, 2878, 1694, 1669, 1403, 1255, 1175, 1133, 1085,773;

¹H-NMR (CDCl₃): 4.90 (bs, 1H), 3.75-3.65 (m, 1H), 3.63-3.55 (m, 2H),3.27 (ddd, J=2.3, 6.2, 8.5 Hz, 1H), 2.16 (dd, J=8.3, 13.1 Hz, 1H),1.82-1.70 (m, 1H), 1.52-1.44 (m, 1H), 1.49 (s, 9H), 0.78-0.68 (m, 1H),0.43-0.35 (m, 1H);

Mass (m/z): 214 [M+H⁺].

Example 1 Preparation of3-(Pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane dihydrochloride Step(i): Preparation of3-(pyridine-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acidtert-butyl ester

To an ice cold solution of triphenylphosphine (1.66 grams, 6.4 mmol) indry tetrahydrofuran (7 mL) was added diethyl azodicarboxylate (1.0 mL,6.4 mmol). The mixture was warmed to room temperature and stirred for 30minutes. The reaction mixture was cooled to 0° C. and a solution of3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butylester (obtained in step (vii) of preparation 1) (0.9 grams, 4.2 mmol) indry tetrahydrofuran (7 mL) was added followed by a solution of3-hydroxypyridine (0.6 grams, 6.4 mmol) in dry tetrahydrofuran (14 mL).The reaction mixture was gradually warmed to room temperature andstirred for 0.16 hours. The volatiles were evaporated under reducedpressure and crude obtained was purified by flash column chromatographyusing 230-400 mesh silica gel to obtain title compound 0.83 grams asgummy liquid. Yield: 68%.

IR (cm⁻¹): 2977, 2933, 2876, 1694, 1575, 1476, 1392, 1257, 1231, 1174,1134, 1023, 801, 759, 707;

¹H-NMR (CDCl₃): 8.32 (d, J=2.6 Hz, 1H), 8.21 (d, J=4 Hz, 1H), 7.24-7.15(m, 2H), 4.28-4.15 (m, 2H), 4.10-3.95 (m, 2H), 2.28 (ddd, J=3.6, 6.8,13.4 Hz, 1H), 2.12 (dd, J=7.8, 13.4 Hz, 1H), 1.49-1.40 (m, 1H), 1.47 (s,9H), 0.92-0.80 (m, 1H), 0.41-0.35 (m, 1H);

Mass (m/z): 291 [M+H⁺].

Step (ii): Preparation of3-(Pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane dihydrochloride

To an ice-cold solution of above obtained compound (1 mmol) indichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and thereaction mixture was stirred for 2 hours. The volatiles were removedunder reduced pressure. The crude product was treated with cold dryhydrochloride (3M) in isopropropanol (2 mL). The solvent was removedunder reduced pressure and the residue was titrated with hexane andether to obtain title compound (0.95 mmol) as dihydrochloride salt.Yield: 95%.

IR (cm⁻¹): 3400, 2868, 2688, 2631, 2586, 2491, 1551, 1278, 1024, 827,799, 676;

¹H-NMR (CD₃OD): 8.69 (d, J=2.1 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.28(dd, J=2.1, 4.0 Hz, 1H), 8.05 (dd, J=4.0, 8.0 Hz, 1H), 4.61 (dd, J=3.0,8.0 Hz, 1H), 4.44 (dd, J=8.0, 9.2 Hz, 1H), 3.97-3.88 (m, 1H), 3.46-3.40(m, 1H), 2.35 (dd, J=8.0, 12.0 Hz, 1H), 2.22-2.12 (m, 1H), 2.0-1.92 (m,1H), 1.13-1.08 (m, 1H), 1.0-0.92 (m, 1H);

Mass (m/z): 191 [M+H⁺].

Example 2 Preparation of2-Methyl-3-(pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane

To a stirred solution of above obtained compound (1 mmol) in formic acid(1 mL) was added formaldehyde (40% w/v, 2 mL) and the reaction mixturewas stirred at 80° C. for 3 hours. The reaction mixture was cooled toroom temperature and pH was adjusted between 8-9 by addition ofsaturated aqueous potassium carbonate. The aqueous layer was extractedwith dichloromethane, the combined organic layer was dried overanhydrous sodium sulphate and the solvent was removed under reducedpressure to obtain crude product which was purified by 230-400 silicagel flash column chromatography to obtain title compound (0.7-0.9 mmol).Yield: 90%.

IR (cm⁻¹): 2942, 2854, 1674, 1574, 1475, 1425, 1277, 1230, 1050, 1024,800, 756, 706;

¹H-NMR (CDCl₃): 8.30 (d, J=2.1 Hz, 1H), 8.21 (dd, J=1.5, 4.0 Hz, 1H),7.20-7.10 (m, 2H), 3.98 (dd, J=5.0, 9.2 Hz, 1H), 3.89 (dd, J=5.5, 9.2Hz, 1H), 2.80 (ddd, J=2.5, 5.8, 8.4 Hz, 1H), 2.47 (s, 3H), 2.47-2.40 (m,1H), 2.20 (dd, J=7.2, 12.5 Hz, 1H), 1.92 (ddd, J=5.0, 10.0, 17.1 Hz,1H), 1.46-1.40 (m, 1H), 0.66-0.62 (m, 1H), 0.20-0.11 (m, 1H);

Mass (m/z): 205 [M+H⁺].

Examples 3-20

The compounds of Examples 3-20 were prepared by following the proceduresas described in Examples 1 to 2, with some non-critical variations.

3. 3-(2-Methylpyridin-3-yl- IR (cm⁻¹): 2946, 2535, 2110, 1669, 1627,1570, 1414, oxymethyl)-2- 1294, 1205, 1179, 1130, 1031, 798, 719;azabicyclo[3.1.0]hexane ¹H-NMR (CD₃OD): 8.21 (d, J = 5.0 Hz, 1H), 7.85(d, J = dihydrochloride; 8.4 Hz, 1H), 7.63 (dd, J = 5.5, 8.3 HZ, 1H),4.52 (dd, J = 3.3, 10.7 Hz, 1H), 4.25 (dd, J = 9.1, 10.7 Hz, 1H), 3.95-3.85 (m, 1H), 3.45-3.97 (m, 1H), 2.61 (s, 3H), 2.40 (dd, J = 7.2, 13 Hz,1H), 2.20-2.10 (m, 1H), 2.0-1.92 (m, 1H), 1.10- 1.02 (m, 1H), 1.0-0.90(m, 1H); Mass (m/z): 205 [M + H⁺]. 4. 3-(2-Chloropyridin-3- IR (cm⁻¹):3411, 3029, 2870, 2481, 1533, 1452, 1334, yloxymethyl)-2- 1296, 1025,999, 846, 827, 807, 721; azabicyclo[3.1.0]hexane ¹H-NMR (D₂O): 7.88 (d,J = 4.3 Hz, 1H), 7.42 (d, J = 8.1 dihydrochloride; Hz, 1H), 7.29 (dd, J= 4.7, 8.1 Hz, 1H), 4.44 (dd, J = 3.2, 10.8 Hz, 1H), 4.10 (dd, J = 8.5,10.8 Hz, 1H), 3.85-3.75 (m, 1H), 3.30-3.23 (m, 1H), 2.25 (dd, J = 7.2,13.0 Hz, 1H), 2.05 (ddd, J = 4.8, 13.0, 16.0 Hz, 1H), 1.85-1.78 (m, 1H),0.90-0.85 (m, 1H), 0.85-0.75 (m, 1H); Mass (m/z): 225, 277 [M + H⁺]. 5.3-(2-Chloropyridin-5- IR (cm⁻¹): 3463, 2887, 2814, 2734, 2586, 2495,1585, yloxymethyl)-2- 1526, 1455, 1310, 1281, 1024, 846, 825, 697, 624;azabicyclo[3.1.0]hexane ¹H-NMR (D₂O): 7.94 (d, J = 2.7 Hz, 1H), 7.35(dd, J = 2.7, dihydrochloride; 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H),4.32 (dd, J = 3.2, 10.8 Hz, 1H), 4.10 (dd, J = 7.6, 10.8 Hz, 1H),3.75-3.65 (m, 1H), 3.28-3.20 (m, 1H), 2.21 (dd, J = 7.2, 13.1 Hz, 1H),2.05 (ddd, J = 4.8, 11.6, 16.0 Hz, 1H), 1.85-1.75 (m, 1H), 0.90-0.85 (m,1H), 0.83-0.74 (m, 1H); Mass (m/z): 225, 227 [M + H⁺]. 6.3-(2-Fluoropyridin-5- IR (cm⁻¹): 3050, 2934, 2717, 2575, 2487, 2453,1609, yloxymethyl)-2- 1586, 1492, 1384, 1290, 1244, 1032, 777;azabicyclo[3.1.0]hexane ¹H-NMR (D₂O): 7.73 (s, 1H), 7.48 (ddd, J = 3.2,6.4, 9.2 dihydrochloride; Hz, 1H), 6.95 (dd, J = 2.4, 9.2 Hz, 1H), 4.31(dd, J = 3.2, 10.8 Hz, 1H), 4.08 (dd, J = 7.6, 10.8 Hz, 1H), 3.77-3.69(m, 1H), 3.28-3.21 (m, 1H), 2.20 (dd, J = 7.2, 13.0 Hz, 1H), 2.05 (ddd,J = 4.7, 11.2, 16.0 Hz, 1H), 1.76-1.69 (m, 1H), 0.94-0.88 (m, 1H),0.87-0,78 (m, 1H); Mass (m/z): 209 [M + H⁺]. 7. 3-(5-Chloropyridin-3- IR(cm⁻¹): 3373, 3022, 2924, 2666, 2615, 2070, 1614, yloxymethyl)-2- 1552,1439, 1290, 1040, 1005, 705, 669: azabicyclo[3.1.0]hexane ¹H-NMR (D₂O):8.24 (s, 1H), 8.21 (s, 1H), 7.72 (s, 1H), dihydrochloride; 4.40 (dd, J =3.2, 10.8 Hz, 1H), 4.16 (dd, J = 7.6, 10.8 Hz, 1H), 3.80-3.70 (m, 1H),3.28-3.21 (m, 1H), 2.20 (dd, J = 7.2, 13.1 Hz, 1H), 2.05 (ddd, J = 4.9,11.7, 16.2 Hz, 1H), 1.88-1.78 (m, 1H), 0.93-0.87 (m, 1H), 0.85-0.75 (m,1H); Mass (m/z): 225, 227 [M + H⁺]. 8. 3-(5-Bromopyridin-3- IR (cm⁻¹):3346, 2996, 2924, 2474, 1546, 1433, 1259, yloxymethyl)-2- 1035, 1010,836, 665; azabicyclo[3.1.0]hexane ¹H-NMR (D₂O): 8.37 (s, 1H), 8.28 (s,1H), 7.97 (s, 1H), tartrate; 4.42 (dd, J = 2.8, 10.7 Hz, 1H), 4.20 (dd,J = 7.6, 10.7 Hz, 1H), 3.80-3.70 (m, 1H), 3.30-3.20 (m, 1H), 2.21 (dd, J= 7.2, 13.0 Hz, 1H), 2.10-2.0 (m, 1H), 1.88-1.78 (m, 1H), 0.95-0.88 (m,1H), 0.87-0.77 (m, 1H); Mass (m/z): 269, 271 [M + H⁺]. 9.3-(2-Fluoropyridin-3- IR (cm⁻¹): 3406, 3337, 3105, 2931, 1741, 1450,1254, yloxymethyl)-2- 1193, 1132, 1085, 942, 6683322, 2975, 2869, 2496,1737, azabicyclo[3.1.0]hexane 1580, 1469, 1404, 1306, 1263, 1133, 1067,790, 678; tartrate; ¹H-NMR (D₂O): 7.64 (d, J = 4.5 Hz, 1H), 7.48 (t, J =9.0, 1H), 7.19 (dd, J = 5.0, 7.7 Hz, 1H), 4.48 (s, 1H), 4.40 (dd, J =2.9, 11.0 Hz, 1H), 4.15 (dd, J = 7.9, 11.0 Hz, 1H), 3.80- 3.70 (m, 1H),3.30-3.22 (m, 1H), 2.25 (dd, J = 7.1, 13.0 Hz, 1H), 2.10-2.0 (m, 1H),1.88-1.78 (m, 1H), 0.96-0.89 (m, 1H), 0.86-0.78 (m, 1H); Mass (m/z): 209[M + H⁺]. 10. 3-(2-Fluoropyridin-3- IR (cm⁻¹): 3406, 3337, 3105, 2931,1741, 1450, 1254, yloxymethyl)-2-methyl-2- 1193, 1132, 1085, 942, 668;azabicyclo[3.1.0]hexane ¹H-NMR (D₂O): 7.68 (d, J = 4.0 Hz, 1H), 7.52 (t,J = 8.8, tartrate; 1H), 7.22 (dd, J = 4.0, 7.6 Hz, 1H), 4.45 (dd, J =3.0, 10.9 Hz, 1H), 4.28 (dd, J = 4.6, 10.9 Hz, 1H), 3.60-3.50 (m, 1H),3.50-3.40 (m, 1H), 3.0 (s, 3H), 2.30-2.25 (m, 2H), 1.90-1.82 (m, 1H),1.13-1.05 (m, 1H), 0.90-0.80 (m, 1H); Mass (m/z): 223 [M + H⁺]. 11.3-(2-Chloropyridin-3- IR (cm⁻¹): 2529, 2494, 1568, 1432, 1401, 1298,1211, yloxymethyl)-2-methyl-2- 1095, 1060, 806, 714;azabicyclo[3.1.0]hexane; ¹H-NMR (D₂O): 7.80 (d, J = 4.8 Hz, 1H), 7.34(d, J = 8.2 Hz, 1H), 7.20 (dd, J = 4.8, 8.2 Hz, 1H), 4.38 (dd, J = 2.5,11.5 Hz, 1H), 4.10 (dd, J = 6.7, 11.5 Hz, 1H), 3.55-3.45 (m, 1H),3.38-3.32 (m, 1H), 2.96 (s, 3H), 2.25-2.15 (m, 2H), 1.80-1.72 (m, 1H),1.0-0.93 (m, 1H), 0.80-0.70 (m, 1H); Mass (m/z): 239, 241 [M + H⁺]. 12.2-Methyl-3-(2-methylpyridin- IR (cm⁻¹): 2669, 2543, 1548, 1466, 1400,1282, 1140, 3-yloxymethyl)-2- 1068, 1023, 807; azabicyclo[3.1.0]hexane;¹H-NMR (CD₃OD): 8.32 (d, J = 5.7 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.88(dd, J = 5.7, 8.6 Hz, 1H), 4.65 (dd, J = 2.2, 11.4 Hz, 1H), 4.56 (dd, J= 6.5, 11.4 Hz, 1H), 3.85- 3.75 (m, 1H), 3.68-3.61 (m, 1H), 3.14 (s,3H), 2.72 (s, 3H), 2.45 (dd, J = 7.2, 13.3 Hz, 1H), 2.40-2.32 (m, 1H),2.0-1.92 (m, 1H), 1.30-1.25 (m, 1H), 1.0-0.92 (m, 1H); Mass (m/z): 219[M + H⁺]. 13. 2-Methyl-3-(2-methylpyridin- IR (cm⁻¹): 2652, 2609, 1616,1559, 1465, 1316, 1289, 5-yloxymethyl)-2- 1024, 996, 841, 757;azabicyclo[3.1.0]hexane; ¹H-NMR (CDCl₃): 8.16 (d, J = 2.7 Hz, 1H), 7.09(dd, J = 2.7, 8.5 Hz, 1H), 7.03 (d, J = 8.5, 1H), 4.07 (dd, J = 6.7,13.5 Hz, 1H), 3.92 (dd, J = 5.0, 9.2 Hz, 1H), 3.86 (dd, J = 5.5, 9.2 Hz,1H), 2.83-2.75 (m, 1H), 2.48 (s, 3H), 2.46 (s, 3H), 2.46-2.38 (m, 1H),2.18 (dd, J = 7.2, 11.0 Hz, 1H), 1.95-1.87 (m, 1H), 1.45-1.38 (m, 1H),0.68-0.60 (m, 1H), 0.20-0.10 (m, 1H); Mass (m/z): 219 [M + H⁺]. 14.3-(2-Chloropyridin-5- IR (cm⁻¹): 2967, 2935, 2381, 1584, 1571, 1454,1445, yloxymethyl)-2-methyl-2- 1274, 1228, 1142, 1033, 832, 819, 698;azabicyclo[3.1.0]hexane; ¹H-NMR (CDCl₃): 8.04 (d, J = 2.7 Hz, 1H), 7.21(d, J = 8.6 Hz, 1H), 7.14 (dd, J = 2.7, 8.6 Hz, 1H), 3.98-3.85 (m, 2H),2.83-2.77 (m, 1H), 2.45 (s, 3H), 2.45-2.40 (m, 1H), 2.17 (dd, J = 7.2,12.4 Hz, 1H), 1.97-1.87 (m, 1H), 1.48- 1.38 (m, 1H), 0.67-0.60 (m, 1H),0.20-0.11 (m, 1H). Mass (m/z): 239, 241 [M + H⁺]. 15.3-(2-Fluoropyridin-5- IR (cm⁻¹): 2966, 2943, 2398, 1604, 1587, 1485,1392, yloxymethyl)-2-methyl-2- 1241, 1052, 1038, 827, 803, 769;azabicyclo[3.1.0]hexane; ¹H-NMR (CDCl₃): 7.80 (s, 1H), 7.38-7.30 (m,1H), 6.84 (dd, J = 3.5, 8.8 Hz, 1H), 3.94 (dd, J = 5.0, 9.1 Hz, 1H),3.88 (dd, J = 5.3, 9.1 Hz, 1H), 2.84-2.73 (m, 1H), 2.46 (s, 3H),2.46-2.40 (m, 1H), 2.17 (dd, J = 7.2, 12.4 Hz, 1H), 1.98-1.88 (m, 1H),1.46-1.38 (m, 1H), 0.68-0.60 (m, 1H), 0.20-0.11 (m, 1H); Mass (m/z): 223[M + H⁺]. 16. 3-(5-Chloropyridin-3- IR (cm⁻¹): 2951, 2867, 2623, 2549,2094, 1619, 1552, yloxymethyl)-2-methyl-2- 1436, 1291, 1022, 910, 874,755, 697, 674; azabicyclo[3.1.0]hexane; ¹H-NMR (CDCl₃): 8.19 (s, 1H),8.18 (s, 1H), 7.20 (s, 1H), 3.95 (dd, J = 5.0, 9.2 Hz, 1H), 3.90 (dd, J= 5.3, 9.2 Hz, 1H), 2.86-2.78 (m, 1H), 2.45 (s, 3H), 2.45-2.40 (m, 1H),2.17 (dd, J = 7.2, 12.4 Hz, 1H), 1.95-1.85 (m, 1H), 1.46- 1.38 (m, 1H),0.68-0.60 (m, 1H), 0.20-0.11 (m, 1H); Mass (m/z): 239, 241 [M + H⁺]. 17.3-(5-Bromopyridin-3- IR (cm⁻¹): 3445, 3010, 2928, 2625, 2522, 1542,1435, yloxymethyl)-2-methyl-2- 1285, 1027, 868, 671;azabicyclo[3.1.0]hexane ¹H-NMR (CDCl₃): 8.27 (s, 1H), 8.23 (s, 1H), 7.35(s, 1H), dihydrochloride; 3.94 (dd, J = 5.0, 9.1 Hz, 1H), 3.89 (dd, J =5.0, 9.0 Hz, 1H), 2.85-2.73 (m, 1H), 2.45 (s, 3H), 2.45-2.40 (m, 1H),2.18 (dd, J = 7.2, 12.5 Hz, 1H), 1.95-1.85 (m, 1H), 1.65- 1.55 (m, 1H),0.70-0.60 (m, 1H), 0.20-0.12 (m, 1H); Mass (m/z): 283, 285 [M + H⁺]. 18.3-(2-Methylpyridin-5- IR (cm⁻¹): 3522, 3443, 2886, 2689, 2588, 2492,1621, yloxymethyl)-2- 1559, 1453, 1407, 1388, 1359, 1276, 1122, 1031,847, 760; azabicyclo[3.1.0]hexane; ¹H-NMR (CD₃OD): 8.49 (bs, 1H), 8.14(bs, 1H), 7.84 (bs, 1H), 4.60-4.50 (m, 1H), 4.48-4.32 (m, 1H), 3.98-3.82(m, 1H), 3.48-3.40 (m, 1H), 2.71 (s, 3H), 2.42-2.32 (m, 1H), 2.25-2.10(m, 1H), 1.32-1.20 (m, 1H), 1.18-1.15 (m, 1H), 1.0-0.90 (m, 1H); Mass(m/z): 205 [M + H⁺]. 19. 3-(Pyridin-3-yloxymethyl)-2- ¹H-NMR (DMSO-d₆):9.70 (bs, 1H), 9.50 (bs, 1H), 8.52 (s, azabicyclo[4.1.0]heptane 1H),8.37 (d, J = 4.6 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.63 hydrochloride;(dd, J = 7.2, 4.6 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H), 3.01- 2.94 (m, 1H),2.80-2.70 (m, 1H), 2.20-2.16 (m, 1H), 1.70- 1.52 (m, 3H), 1.28-1.10 (m,1H), 0.92-0.82 (m, 1H); Mass (m/z): 205 [M + H⁺]. 20.3-(5-Chloropyridin-3- ¹H-NMR (DMSO-d₆): 9.68 (bs, 1H), 9.44 (bs, 1H),8.34 (d, yloxymethyl)-2- J = 2.3 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.71(dd, J = 2.3, azabicyclo[4.1.0]heptane 1.7 Hz, 1H), 4.28 (d, J = 5.1 Hz,2H), 3.50-3.40 (m, 1H), hydrochloride; 2.82-2.72 (m, 1H), 2.18-2.05 (m,1H), 1.70-1.45 (m, 3H), 1.30-1.18 (m, 1H), 0.95-0.82 (m, 1H); Mass(m/z): 239, 241 [M + H⁺].

Examples 21-49

The person skilled in the art can prepare the compounds of Examples21-49 by following the procedures described above.

21. 5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acidamide; 22. 5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylicacid; 23. 3-(2-Methoxypyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;24. 3-(2-Isopropoxypyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane; 25.[5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]-methanol; 26.3-(2-Methoxymethylpyridin-5-yloxymethyl)-2- azabicyclo[3.1.0]hexane; 27.[5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin- 2-ylmethyl]methylamine;28. 5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acid amide; 29.5-(2-Methy]-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine- 2-carboxylicacid; 30. 3-(2-Methoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane; 31.3-(2-Isopropoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane; 32.[5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin- 2-yl]methanol;33. Methyl-[5-(2-methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-ylmethyl]amine: 34.5-[1-(2-Azabicyclo[3.1.0]hex-3-yl)-ethoxy]pyridin-2-ylamine; 35.{5-[1-(2-Azabicyclo[3.1.0]hex-3-yl)-ethoxy]pyridin- 2-yl}methylamine;36. [5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin- 2-yl]dimethylamine;37. 3-(2-Pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane; 38.5-[1-(2-Methyl-2-azabicyclo[3.1.0]hex-3-yl)ethoxy]pyridin- 2-ylamine;39. Methyl-{5-[1-(2-methyl-2-azabicyclo[3.1.0]hex-3-yl)ethoxy]pyridin-2-yl}amine; 40.Dimethyl-[5-(2-methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridin-2-yl]amine; 41.2-Methyl-3-(2-pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane; 42.3-(Pyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane; 43.3-(6-Methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane; 44.3-(2-Methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane; 45.3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane; 46.2-Methyl-3-(2-methylpyridin-3-yloxymethyl)-2- azabicyclo[4.1.0]heptane;47. 3-(5-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[4.1.0]heptane; 48.4-[2-(Pyridin-3-yloxy)ethyl]-2-azabicyclo[3.1.0]hexane; 49.4-[2-(5-Chloropyridin-3-yloxy)ethyl]-2-methyl-2-azabicyclo[3.1.0]hexane;

Biological Assays Example 50 Binding assay for Human or Rat NicotinicAcetylcholine α₄β₂ receptor

Compounds can be evaluated according to the following procedures.

Materials and Methods:

-   -   Receptor source: Rat brain frontal cortex or recombinant human        cDNA expressed in CHO cells    -   Radioligand: [³H] Cytisine 15-40 Ci/mmol    -   Final ligand concentration—[2.5 nM]    -   Non-specific determinant: Epibatidine-[0.1 μM]    -   Reference compound: Epibatidine    -   Positive control: Epibatidine

Incubation Conditions:

Increasing concentrations of test compounds or standard were incubatedwith membrane receptors and radioligand in 120 mM NaCl, 2.5 mM KCl, 1 mMCaCl₂, 1 mM MgCl₂ and 50 mM TRIS-HCl (pH 7.4) for 60 minutes at roomtemperature. The reaction was terminated by rapid vacuum filtration ontothe glass fiber filters. Radioactivity trapped onto the filters wasdetermined and compared to the control values in order to ascertain anyinteractions of the test compound(s) with either cloned human or ratreceptor binding site.

Example Number K_(i) (nM) 1. 7.7 2. 5.5 3. 1000 4. 17.5 5. 1.5 6. 3.9 7.0.19 8. 6.4 9. 17.4 10. 31.9 11. 28.1 12. 231 13. 0.3 14. 3.4 15. 1.116. 0.37 17 4.2 18. 26.15 19. 8.2 20. 215.7

Literature Reference: Bunnelle W. H., Daanen J. F., Ryther K. B.,Schrimpf M. R., Dart M. J., Gelain A., Meyer M. D., Frost J. M.,Anderson D. J., Buckley M., Curzon P., Cao Y-J., Puttfarcken P., SearleX., Ji J., Putman C. B., Surowy C., Toma L. and Barlocco D.Structure-Activity Studies and Analgesic Efficacy ofN-(3-Pyridinyl)-Bridged Bicyclic Diamines, Exceptionally Potent Agonistsat Nicotinic Acetylcholine Receptors. J. Med. Chem. 2007, 50, 36-27.

Example 51 Determination of IC₅₀ and K_(b) Values for NicotinicAcetylcholine α₄β₂ Receptor Ligands

A stable CHO cell line expressing recombinant human α₄β₂ nicotinicacetylcholine receptor transiently expressing aequorin protein was usedfor cell-based assay. The assay offers a non-radioactive based approachto determine binding of a compound to ligand gated ion channels. In thisspecific assay, the level of intracellular calcium which is modulated byactivation or inhibition of the channel is measured. Both the channeland aequorin genes are expressed at high level under the control ofpowerful CMV promotor.

The above cells were grown in 96 well clear bottom white plates in HamsF12 medium containing 10% fetal bovine serum (FBS). Prior to theaddition of compounds and/or agonist, cells were serum starved for sixhours. Coelentarazine (a prosthetic group for aequorin protein) wasadded in the medium containing 0.1% dialyzed serum and incubatedovernight at 27° C. Cells were washed with assay buffer and increasingconcentration of the test compound or standard were added to the platefor antagonist mode. A fixed concentration of the agonist (eipbatidine)was injected into the plate and luminescence was measured for 10seconds. For evaluation of the compound in agonist mode, increasingconcentration of the standard or test compound was injected and theluminescence was measured. Luminescence units were plotted against thecompound concentrations using Graphpad software. IC₅₀ values of thecompounds were defined as the concentration required in reducing theluminescent units by 50%. The K_(b) values were calculated by feedingthe concentration of the agonist used in the assay and its EC₅₀ value inthe same software.

Example Number K_(b) (nM) 1. 7.1 2. 0.4 7. 17.8 11. 13.5 13. 5 16. 0.418. 22

Literature References: Karadsheh M. S., Shah M. S., Tang X., MacdonaldR. L. and Stitzel J. A. Functional characterization of mouse α₄β₂nicotinic acetylcholine receptors stably expressed in HEK293T cells. J.Neurochem. 2004, 91, 1138-1150.

Example 52 Rodent Pharmacokinetic Study

Male wistar rats (230-280 grams) obtained from NIN (National Instituteof Nutrition, Hyderabad, India) were used as an experimental animal.Three to five animals were housed in each cage. Animals were kept fastedover night and maintained on a 12 hours light/dark cycle. Three ratswere dosed NCE orally (15 mg/Kg) and intravenously (5 mg/Kg) on day 0and day 2.

At each time point blood was collected by jugular vein. Plasma wasstored frozen at −20° C. until analysis. The concentrations of the NCEcompound in plasma were determined using LC-MS/MS method. Schedule timepoints: Pre dose 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hoursafter dosing (n=3). The NCE compounds were quantified in plasma byvalidated LC-MS/MS method using solid phase extraction technique. NCEcompounds were quantified in the calibration range of 1-2000 ng/mL inplasma. Study samples were analyzed using calibration samples in thebatch and quality control samples spread across the batch.Pharmacokinetic parameters C_(max), T_(max), AUC_(s), T₁₁₂ andBioavailability were calculated by non-compartmental model usingsoftware WinNonlin version 5.0.1.

Example Strain/ Dose Route of C_(max) T_(max) AUC_(t) T_(1/2)Bioavailability Number Gender (mg/kg) Vehicle administration (ng/mL) (h)(ng · hr/mL) (h) (%) 1. Wister rat/ 15 Water for P.O  7611 ± 1660 0.25 ±0.00 10925 ± 646  4.19 ± 1.53 92 ± 16 Male injection Wister rat/ 5 Waterfor I.V 3185 ± 38  0.08 ± 0.00 4049 ± 679 1.94 ± 0.62 Male injection 4.Wister rat/ 5 Water for P.O  921 ± 268 0.25 ± 0.00 2158 ± 658 2.15 ±0.51 54 ± 23 Male injection Wister rat/ 5 Water for I.V 2601 ± 42  0.08± 0.00 4165 ± 878 1.55 ± 0.25 Male injection 5. Wister rat/ 5 Water forP.O 1906 ± 675 0.25 ± 0.00 3507 ± 657 3.34 ± 0.60 66 ± 12 Male injectionWister rat/ 5 Water for I.V 2724 ± 588 0.08 ± 0.00 5381 ± 821 2.52 ±0.43 Male injection 7. Wister rat/ 5 Water for P.O  949 ± 200 0.25 ±0.00 1188 ± 201 1.07 ± 0.04 50 ± 13 Male injection Wister rat/ 5 Waterfor I.V 2341 ± 388 0.08 ± 0.00 2390 ± 196 0.86 ± 0.03 Male injection

Example 53 Rodent Brain Penetration Study

Male Wistar rats (230-280 grams) obtained from NIN (National Instituteof Nutrition, Hyderabad, India) was used as an experimental animal.Three animals were housed in each cage. Animals were given water andfood ad libitum throughout the experiment, and maintained on a 12 hourslight/dark cycle.

NCE compound was dissolved in water and administered orally. At T_(max)(0.5, 1.0 and 2.0) animals were sacrificed to collect the plasma andbrain tissue and was homogenized. Plasma and Brain was stored frozen at−20° C. until analysis. The concentrations of the NCE compound in plasmaand Brain were determined using LC-MS/MS method.

The NCE compounds were quantified in plasma and brain homogenate byvalidated LC-MS/MS method using solid phase extraction technique. NCEcompounds were quantified in the calibration range of 1-500 ng/mL inplasma and brain homogenate. Study samples were analyzed usingcalibration samples in the batch and quality control samples spreadacross the batch. Extents of brain-blood ratio were calculated(C_(b)/C_(p)).

Steady State Route of Brain Example Strain/ Dose adminis- PenetrationNumber Gender (mg/kg) Vehicle tration (C_(b)/C_(p)) 1. Wistar rat/ 15Water for P.O 3.803 ± 0.289 Male injection Wistar rat/ 5 Water for I.VMale injection 4. Wistar rat/ 5 Water for P.O 3.60 ± 0.99 Male injectionWistar rat/ 5 Water for I.V Male injection 5. Wistar rat/ 5 Water forP.O 2.34 ± 0.25 Male injection Wistar rat/ 5 Water for I.V Maleinjection 7. Wistar rat/ 5 Water for P.O 3.79 ± 0.66 Male injectionWistar rat/ 5 Water for I.V Male injection

Example 54 Object Recognition Task Model

The cognition-enhancing properties of compounds of this invention wereestimated using a model of animal cognition: the object recognition taskmodel.

Male Wister rats (230-280 grams) obtained from N. I. N. (NationalInstitute of Nutrition, Hyderabad, India) was used as experimentalanimals. Four animals were housed in each cage. Animals were kept on 20%food deprivation before one day and given water ad libitum throughoutthe experiment and maintained on a 12 hours light/dark cycle. Also therats were habituated to individual arenas for 1 hour in the absence ofany objects.

One group of 12 rats received vehicle (1 mL/Kg) orally and another setof animals received compound of the formula (I) either orally or i.p.,before one hour of the familiar (T1) and choice trial (T2).

The experiment was carried out in a 50×50×50 cm open field made up ofacrylic. In the familiarization phase, (T1), the rats were placedindividually in the open field for 3 minutes, in which two identicalobjects (plastic bottles, 12.5 cm height×5.5 cm diameter) covered inyellow masking tape alone (a1 and a2) were positioned in two adjacentcorners, 10 cm. from the walls. After 24 hours of the (T1) trial forlong-term memory test, the same rats were placed in the same arena asthey were placed in T1 trial. Choice phase (T2) rats were allowed toexplore the open field for 3 minutes in presence of one familiar object(a3) and one novel object (b) (Amber color glass bottle, 12 cm high and5 cm in diameter). Familiar objects presented similar textures, colorsand sizes. During the T1 and T2 trial, explorations of each object(defined as sniffing, licking, chewing or having moving vibrissae whilstdirecting the nose towards the object at a distance of less than 1 cm)were recorded separately by stopwatch. Sitting on an object was notregarded as exploratory activity, however, it was rarely observed.

T1 is the total time spent exploring the familiar objects (a1+a2).T2 is the total time spent exploring the familiar object and novelobject (a3+b).The object recognition test was performed as described by Ennaceur, A.,Delacour, J., 1988, A new one-trial test for neurobiological studies ofmemory in rats—Behavioural data, Behay. Brain Res., 31, 47-59.Some representative compounds have shown positive effects indicating theincreased novel object recognition viz; increased exploration time withnovel object and higher discrimination index.

Exploration time Example Dose mean ± S.E.M (sec) Number mg/kg, p.o.Familiar object Novel object Inference 1. 0.1 mg/kg 7.75 ± 0.84 12.65 ±1.96 Active 7.   1 mg/kg 6.81 ± 1.49 16.70 ± 3.19 Active

Example 55 Water Maze

Water maze consisted of a 1.8 m diameter; 0.6 m high circular water mazetub filled with water. A platform was placed 1.0 cm below the watersurface in the center of one of the four imaginary quadrants, whichremained constant for all the rats. Rats were administered with vehicleor test compound before acquisition training and half hour afteradministration of vehicle or test compound; scopolamine wasadministered. Rats were lowered gently, feet first into water. A rat wasallowed to swim for 60 seconds to find the platform. If the platform wasfound during this time the trial was stopped and rat was allowed to stayon platform for 30 seconds before being removed from the maze. If theplatform was not found during 60 seconds trials, then the rat wasmanually placed on the platform. Each rat received 4 trials in a day.Retention of the task was assessed on 5th day in which each animalreceived a single 120 seconds probe trial in which platform removed fromthe pool. Time spent in target quadrant (ms) (quadrant in which platformis placed during acquisition training was calculated for probe trial.Latency to reach the platform (ms), swim speed (cm/s) and path length(cm) was measured in acquisition trials.

Example 56 Mouse Forced Swim Assay

The animals were administered with vehicle or test drug prior totesting. Then the animals were individually placed inside the plexiglasscylinder containing water for 6 min. The initial 2 minutes will be notbe scored and remaining 4 minutes was observed for immobility behavior.Immobility behavior is defined as no movement of animal except littleaction to keep the head above the water level. The water was changedafter every trial.

Example 57 DRL-72s

The antidepressant properties of compounds of this invention wereevaluated using a model of animal depression: the DRL-72s model. MaleSprague Dawley rats were used as experimental animals. Rats are trainedto lever press for a 4″ access to 0.025 mL of water for each correctresponse during daily 60 minute sessions. All testing takes place onweekdays only. At the beginning of each session, the house light isilluminated and remains lit until the session ends. No other stimuli arepresented during testing. After successful lever press training, ratsare then required to respond under a DRL-24 second schedule, where onlylever presses that are separated by 24 seconds are reinforced. Uponstable responding on a DRL-24 second schedule (5-10 sessions), rats aretrained on a DRL-72 second schedule until responding stabilizes atapproximately 15% efficiency (approx 25-35 sessions). Specifically, ratsreceive a reinforcer for each response that is emitted at least 72seconds after the previous response (IRT). Responses with IRT's lessthan 72 seconds do not receive a reinforcer, and the IRT requirement isreset to 72 seconds. Efficiency is recorded as number of reinforcedresponses÷total number of responses. After stable baseline responding isachieved, defined as responding for 4 consecutive sessions with no morethan 10% variability, animals begin drug testing. Animals receive drugno more than 1× per week.

Example Number Dose mg/kg, p.o. 1. ≦10 mg/kg, p.o.

Example 58 Reversal of Formalin Induced Nociception

The anti-nociceptive properties of compounds of this invention wereevaluated using a model of pain: the Formalin Induced Nociception model.Male Wister rats (230-280 grams) obtained from N. I. N. (NationalInstitute of Nutrition, Hyderabad, India) was used as experimentalanimals.

Rats were habituated for 20 minutes in the arena before the experimentwas started. Duration of licks, bites and flinches were noted from 0-10minutes and 20-35 minutes after administration of formalin, subplantarinto the right hind paw at concentrations of 5% v/v. 50 μL of water forinjection was injected into the right hind paw of the rats of the shamgroup. Compounds of this invention were administered orally prior toformalin administration.

Example Number Dose 1. ≦10 mg/kg, p.o. 6. ≦30 mg/kg, p.o. 7. ≦30 mg/kg,p.o.

Example 59 Acute Food Intake Study

The appetite suppressing properties of compounds of this invention werestudied using an animal model of hyperphagia.

Male Wistar rats (200-210 grams) obtained from Raj Biotech, India wereused as experimental animals. The experiment consisted of 6 days. Therats were adapted to the 18 hour fasting and 6 hour feeding pattern. Theanimals were housed in a group of three in the cages provided with thefasting grills and were fasted for 18 hours. After 18 hour fasting therats were separated and placed individually in a cage. Weighed amount offeed was provided to rats for 6 hour and the feed intake at 1, 2, 4 and6 hours was recorded. Again the rats were regrouped and fasted for 18hour. The above procedure was followed for 5 days. The averagecumulative food intake by the rats on the last 3 days was calculated.Animals were randomised on the basis of their last three days foodintake.

One group of 8 rats received vehicle (2 mL/Kg) orally and another set ofanimals received compound of the formula (I) orally. Then the rats weregiven access to food and the food intake at 1, 2, 4 and 6 hours wasrecorded. The food intake by the rats treated with test compound wascompared with the vehicle treated group by using students ‘t’ test.

Following compound shown positive effects indicating the suppression offood intake i.e. hypophagia like effects.

Example % Suppression of food intake compared to vehicle Number 1 Hour 2Hour 4 Hour 6 Hour Inference 1. 32.25% 25.40% 23.08% 15.37% Active

Example 60 Effect of Test Compounds on Body Weight Gain in High Fat FedRats

The body weight gain suppressing properties of compounds of thisinvention were studied using a animal model of obesity.

Male Sprague Dawley rats (150-160 grams) obtained from Reliance LifeSciences, India were used as experimental animals. Rats were fed withcontrol diet (normal pellet diet) and lard based high fat diet (45% kcaldiet) for 7-8 weeks. High fat diet fed animals was randomized accordingto their body weights. The animals were housed in a group of 3-4 percage. One group of 10 rats received vehicle (2 mL/Kg) orally and anotherset of animals received compound of the formula (I) orally for 14 days.Body weight of the animals was recorded for first three consecutive daysthen it was recorded twice weekly. Weighed amount of food was given tothe animals and food intake was recorded every 24 hour for the entirestudy period.

Following compound shown positive effects indicating the decrease in thebody weight gain.

% Reduction in body weight gain compared to vehicle Example Number (Day14) Inference 1. 3.6% Active

1-17. (canceled)
 18. A compound of the general formula (I):

wherein, R is heteroaryl; at each occurrence, R₁ is independentlyselected from hydrogen or alkyl; at each occurrence, R₂ is independentlyselected from hydrogen, alkyl or alkoxy; at each occurrence, R₃ isindependently selected from hydrogen, hydroxy, halogen, amide, amine,carboxylic, alkyl, alkoxy, haloalkyl, haloalkoxy or heterocyclyl; “m” isan integer 1; “n” is an integer ranging from 1 to 2; “p” is an integerranging from 1 to 2; or their stereoisomers or pharmaceuticallyacceptable salts.
 19. The compound according to claim 18, wherein R₂ ishydrogen or alkyl.
 20. The compound according to claim 18, wherein R₃ ishydrogen, hydroxy, halogen, amide, amine, carboxylic, alkyl, alkoxy orheterocyclyl.
 21. The compound according to claim 18, which is selectedfrom the group consisting of:3-(Pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane dihydrochloride;2-Methyl-3-(pyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;3-(2-Methylpyridin-3-yl-oxymethyl)-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(2-Chloropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(2-Chloropyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(2-Fluoropyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(5-Bromopyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane tartrate;3-(2-Fluoropyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane tartrate;3-(2-Fluoropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexanetartrate;3-(2-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;2-Methyl-3-(2-methylpyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;2-Methyl-3-(2-methylpyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;3-(2-Chloropyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;3-(2-Fluoropyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;3-(5-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;3-(5-Bromopyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexanedihydrochloride;3-(2-Methylpyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acid amide;5-(2-Azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylic acid;3-(2-Methoxypyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;3-(2-Isopropoxypyridin-3-yloxymethyl)-2-azabicyclo[3.1.0]hexane;5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylicacid amide;5-(2-Methyl-2-azabicyclo[3.1.0]hex-3-ylmethoxy)pyridine-2-carboxylicacid;3-(2-Methoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;3-(2-Isopropoxypyridin-5-yloxymethyl)-2-methyl-2-azabicyclo[3.1.0]hexane;5-[1-(2-Azabicyclo[3.1.0]hex-3-yl)-ethoxy]pyridin-2-ylamine;3-(2-Pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane;5-[1-(2-Methyl-2-azabicyclo[3.1.0]hex-3-yl)ethoxy]pyridin-2-ylamine;2-Methyl-3-(2-pyrrolidin-1-yl-pyridin-5-yloxymethyl)-2-azabicyclo[3.1.0]hexane;3-(Pyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;3-(6-Methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;3-(2-Methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;2-Methyl-3-(2-methylpyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane;3-(5-Chloropyridin-3-yloxymethyl)-2-methyl-2-azabicyclo[4.1.0]heptane;4-[2-(Pyridin-3-yloxy)ethyl]-2-azabicyclo[3.1.0]hexane;4-[2-(5-Chloropyridin-3-yloxy)ethyl]-2-methyl-2-azabicyclo[3.1.0]hexane;3-(Pyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptane hydrochloride;3-(5-Chloropyridin-3-yloxymethyl)-2-azabicyclo[4.1.0]heptanehydrochloride; or their stereoisomers or pharmaceutically acceptablesalts.
 22. A process for the preparation of a compound of formula (I) asclaimed in claim 18, which comprises: (a) reacting the compound offormula (8) with hydroxyl compound of formula (9),

to form a compound of formula (10),

(b) converting the compound of formula (10) to deprotected compound offormula (11),

(c) converting the compound of formula (11) to compound of formula (I),optionally converting the compound of formula (I) to their stereoisomersor pharmaceutically acceptable salts by using known methods.
 23. Apharmaceutical composition comprising a compound according to claim 1 ora pharmaceutically acceptable carrier, diluent, recipient or solvatealong with a therapeutically effective amount of a compound according toclaim
 18. 24. The pharmaceutical composition according to claim 23, forthe treatment of clinical conditions such as cognitive disorders,depression, pain or obesity.
 25. A method for the treatment of adisorder of the central nervous system related to or affected by theα₄β₂ nicotinic receptor, in a patient in need thereof, which comprisesproviding to said patient a therapeutically effective amount of acompound of formula (I) as defined in claim
 1. 26. The method accordingto claim 25, wherein the said disorder is cognitive disorders,depression, pain or obesity.